# 2002 Oxford University Press
Human Molecular Genetics, 2002, Vol. 11, No. 10
1215–1218
Studies of mechanosensation using the fly
Andrew P. Jarman1*
1
The Wellcome Trust Centre for Cell Biology, Institute of Cell and Molecular Biology, University of Edinburgh, King’s
Buildings, Edinburgh EH9 3JR, UK
Received February 18, 2002; Accepted March 11, 2002
ANATOMY OF MECHANOSENSATION
As an arthropod, Drosophila has a tough, mechanically
resistant exoskeleton, which is not conducive to sensation of
touch, and so this modality is largely detected via a battery of
specialised mechanoreceptive sense organs inserted in the
cuticle (external sense organs) (1). These are most noticeable as
the sensory bristles that cover the fly (Fig. 1A). These organs
are modifications of a basic structure that is also used for
gustatory and olfactory sense organs. Each one consists of one
or a few ciliated sensory neurons (type I neurons) innervating a
structure formed by three specialised support cells, such as the
bristle in its socket (Fig. 1B). Characteristically the neuronal
dendrite has an axonemal segment with a 9 2 þ 0 arrangement of microtubules.
A distinct version of the type I sense organ is the chordotonal
organ. In these internal proprioceptors, the neuron is typically
suspended via its support cells between two areas of cuticle to
allow detection of the relative movement of different cuticular
structures; the dendrite is encased in a rigid scolopale structure
(Fig. 1C and F). Unlike external sense organs, chordotonal
organs are normally in organised arrays. A particularly large
array within the antenna (called Johnston’s organ) is adapted to
detect sound transduced via vibration of the antennal capsule,
as well as attitude with respect to gravity (2). Developmental
and comparative studies suggest that external sense organs and
chordotonal organs have a common evolutionary origin (3). It
is probable that each mechanoreceptor type arose from
exaggerations or reductions of different structural features
found in a more generic primordial sense organ.
Although this brief review concentrates on type I sensory
neurons, Drosophila also has non-ciliated sensory neurons
(type II multiple dendritic neurons), which are not associated
with specialised sensory structures. These neurons may be pain
receptors, but they also have certain similarities with the major
non-ciliated touch neurons in C. elegans and so may be touch
sensitive (for instance, innervating the gut or the flexible larval
cuticle).
Drosophila type I sensory neurons are strongly reminiscent
of ciliated mechanosensitive cells in other organisms, including
amphid neurons in C. elegans and cells associated with hearing
in vertebrates (hair cells). In particular there is interest in the
possibility that they represent a model of hair cell structure and
function. There are many differences between these cells as
well as intriguing similarities and it is not yet clear which of
these is the more significant. Hair cells transduce sound via
groups of stereocilia, which are not true axonemal cilia but
are actin-rich outgrowths from microvilli; however these cells
also have a true kinocilium with a 9 þ 2 arrangement of
microtubules.
PHYSIOLOGY OF MECHANOSENSATION
Significantly, the type I sensory dendrite and hair cell
stereocilia are both bathed in a characteristic high Kþ , low
Ca2þ endolymph secreted by the supporting cells (4). For type I
neurons it is envisaged that movement of the ciliated dendrite
relative to surrounding structures causes the opening of cation
channels and an inrush of Kþ , leading to neuronal depolarisation. This can readily be recorded during the deflection of
individual adult bristles (5). Interestingly, depolarisation latencies of 200 ms have been recorded in a recent study, which is
far too fast for any known second messenger cascade (6).
Thus, unlike gustation, olfaction and photoreception,
mechanotransduction may involve the direct gating of the ion
*To whom correspondence should be addressed. Tel: þ 44(0)131 650 7112; Fax: þ 44(0)131 650 7027; Email: [email protected]
Downloaded from http://hmg.oxfordjournals.org/ at Pennsylvania State University on February 27, 2014
Mechanosensation requires the transduction of mechanical stimuli into neuronal impulses. It encompasses
not only the sense of touch but also proprioception and hearing. In contrast to sight, smell and taste,
relatively little is known about the molecular machinery of mechanosensation. It is already clear, however,
that important aspects are conserved across phyla, from Caenorhabditis elegans to humans. Drosophila
melanogaster is well placed to make a significant contribution to this field. Its advantages include a
sequenced genome allied with powerful genetic techniques, and the ability to conduct electrophysiological
recording from mechanoreceptor neurons. For human geneticists, it is expected that Drosophila studies will
provide a source of candidate genes whose human homologues can be examined for roles in
mechanosensory development, function and disease.
1216
Human Molecular Genetics, 2002, Vol. 11, No. 10
channels by mechanical force. This has been taken to suggest
that mechanotransduction conforms to the gating-spring model
proposed for the action of hair cell stereocilia (7,8). This model
posits the existence of an ion channel anchored under tension
between the dendritic cytoskeleton and the extracellular
dendritic cap (an ECM structure secreted by the scolopale/
sheath cell) (6) (Fig. 1D). Movement of one anchor relative to
the other would ‘pull’ the channel open. Such a model also
incorporates an explanation of adaptation – the process by
which sensory receptors can ‘learn’ to ignore a sustained preexisting stimulus and adjust their dynamic range to respond to
a new or additional stimulus. Adaptation to a sustained
deflection has been demonstrated for bristles by electrophysiology (6). In terms of the gating-spring model, adaptation is
perceived as a sliding of the intracellular channel anchor along
the cytoskeleton to ‘reset’ the tension on the channel, and it is
easy to envisage how a molecular motor could be involved.
Interestingly, differences in adaptation speed could provide a
mechanism for sensory specialisation among different chordotonal organs. Electrophysiological studies on larger insects
have provided evidence for different chordotonal neurons
responding to stretch position (activated throughout the
duration of the stretch) or velocity (activated only during the
stretching movement), or even acceleration (activated only at
the start of a stretching movement) (e.g. ref. 9). A mechanism
could be that these simply reflect differing speeds of channel
sliding during adaptation (slow for position-dependent, fast for
velocity-dependent).
GENETICS OF MECHANOSENSATION
A prime advantage of Drosophila as a model of mechanosensation is the potential for genetic screens to discover
molecular components. This was demonstrated by the behavioural screens for mutants that exhibited either touch
insensitivity as larvae or adult uncoordination (indicative of
gross mechanosensory deficit) (10). If one is interested
specifically in mechanotransduction, the downside of these
kinds of assay is that they could detect mutations that alter the
development or function of any step in the touch pathway (from
sensory structure, to sensory transduction, to CNS processing,
Downloaded from http://hmg.oxfordjournals.org/ at Pennsylvania State University on February 27, 2014
Figure 1. (A) Adult Drosophila melanogaster, showing the sensory bristles (external sense organs); also indicated are the locations of some internal chordotonal
organs and Johnston’s Organ, the auditory organ. (B, and C) Cartoons of an external sense organ and a chordotonal organ showing important structural features and
emphasising their similarities (cell sizes are exaggerated for illustration). Deflection of the bristle or stretching of the chordotonal organ impinge on the ciliated
dendrite of the sensory neuron. (D) Gating-spring model for mechanotransduction adapted for Drosophila (based on ref. 8). This represents a hypothetical depiction
of the dendrite surface relative to the dendritic cap. (E, and F) Localisation of GFP-NompA protein (green fluorescence signal) to sense organ dendritic caps (see
ref. 13). (E) External sense organ from the thorax; approximate position of unlabelled sensory neuron is indicated in yellow (F) Two chordotonal organ arrays from
the abdomen (bracketed, with some of the scolopale structures indicated). Each scolopale is associated with a dendritic cap, and each would be associated with a
neuron (unlabelled), the approximate location of one being outlined in yellow.
Human Molecular Genetics, 2002, Vol. 11, No. 10
(downstream) channel activated in response to the (unknown)
mechanically gated channel, particularly since there remains
some residual channel activity in a nompC null mutant (6),
especially in chordotonal organs (11). Important unresolved
questions include the cellular location of NompC, which will
give a clue as to its function. It is encouraging that a C. elegans
NompC homologue has been located at low resolution in the
ciliated dendrites of amphid neurons (6). Finding the proteins
with which NompC interacts extra- and intracellularly will be
crucial. It is notable that the predicted vertebrate spring-gated
channel has not yet been identified, and so the many vertebrate
TRP members are candidates.
The nompA mutation has also been characterised recently (13).
The structural basis for the lack of mechanoreceptor potential
was found to be detachment of the dendrite from the bristle.
Fittingly, NompA is a ZP domain-containing protein that is a
key component of the dendritic caps of bristles and chordotonal
organs (14) (Fig. 1E and F), and is a candidate for the
extracellular component that tethers the ion channel (Fig. 1D).
Other components of the mechanosensation machinery are
likely to include specialised cytoskeletal proteins (such as
MAPs), motors, and cell junction molecules. Some such
molecules are very important for hair cell cytoarchitecture,
including a number of myosins (15). Will these be important in
Drosophila sense organs, even though the cilium is tubulinbased? Preliminary evidence suggests that mutation of
unconventional myosin VIIa (crinkled) causes complete deafness (S.V. Todi and D.F. Eberl, personal communication). The
human homologue of this gene is responsible for the deafness
syndrome, Usher Syndrome 1B.
Although little is known, type II non-ciliated neurons appear
to have a distinct mechanism of mechanotransduction. Some
are known to express a member of the DEG/EnaC family of
Naþ channels (pickpocket) (16). Some vertebrate members of
this family are implicated in touch, and members were
identified (as degenerins) in the touch screens of C. elegans,
which dissected the function of its non-ciliated body-touch
neurons. Thus there may be two separate mechanisms for
mechanosensation, both of which may be conserved in
principle across several phyla.
MOLECULES OF MECHANOSENSATION
Only a few mechanosensation protein components have been
characterised so far, but these few are very significant. As
intimated above, the nomp genes are now known to encode
mechanotransduction molecules required in both bristles and
chordotonal organs. The nompC gene product is a cation
channel belonging to the TRP family, with six transmembrane
domains and a ion pore loop. Mechanoreceptor potentials are
strongly reduced in the null nompC mutant, making it a
candidate for the spring-gated channel. This is notably
supported by the presence of 29 ankyrin repeats in the NompC
protein intracellular domain – the largest number known of
any protein (6) and giving plenty of scope for interaction with
cytoskeleton and/or intracellular adaptation machinery
(Fig. 1D). But NompC has little extracellular domain and it
is suggested that another unidentified protein in a multimeric
channel complex could provide the platform for the extracellular link. Another possibility is that NompC is a secondary
DEVELOPMENTAL GENETICS OF
MECHANOSENSATION
The precursor cells of all Drosophila type I sense organs are
specified by the expression of transcription factors of the bHLH
class (proneural proteins), including achaete-scute for external
sense organs and atonal for chordotonal organs (17).
Specification by variants of a single protein class supports
the impression that sense organs differ from each other by
relatively few gene products or even by quantitative differences
rather than qualitative ones. An outstanding problem is that
there is very little understanding of the genetic pathways that
link these lofty regulatory factors with the ultimate components
of sense organ structure and function. These pathways clearly
involve the homeodomain transcription factor, Cut, which is
activated by achaete-scute and inhibited by atonal (18). Cut is
most strongly implicated in controlling support cell morphology,
Downloaded from http://hmg.oxfordjournals.org/ at Pennsylvania State University on February 27, 2014
to generation of effector motor signals). Nevertheless, many of
the mutations isolated were clearly demonstrated to lack bristle
mechanoreceptor potentials, pointing to a primary sensory
defect (10). These include uncoordinated, uncoordinated-like,
and no mechanoreceptor potential (nompA–D). Most of them
remain to be characterised molecularly.
Interestingly, all but one of the mutations that had reduced or
absent bristle mechanoreceptor potentials were later shown to
have defective hearing too (lack of sound-evoked antennal
potentials), suggesting that the genes encode components
common to the mechanotransduction apparatus of both bristles
and chordotonal organs (11), thereby supporting the strong
structural and functional connection between these sense
organs. One mutation showed a chordotonal-specific transduction defect. This mutation, touch-insensitive-larva B (tilB) was
originally characterised through a reduced larval response to
touch (10), even though it generates normal bristle mechanoreceptor potentials.
Eberl et al. carried out a separate specific screen for mutant
flies defective in hearing (12). To screen for hearing loss, these
authors assayed a behaviour that relies on the wing-generated
auditory cue that male Drosophila use during courtship (socalled love song). Male Drosophila vigorously court one
another if experimentally presented with a recording of the
courtship song, thereby giving a rapid and non-invasive assay
of mutagenised flies. Many of the isolated ‘courtship defective’
mutants showed normal sound-evoked antennal potentials,
suggestive of defects neurally downstream of mechanotransduction (11). One mutation lacked sound-evoked potentials and
was named, inevitably, beethoven (btv) (11). This deaf mutant
has ultrastructural defects in the dendritic cilia of chordotonal
organs, but its molecular identity is not yet known.
These screens have demonstrated the utility of the genetic
approach, but have so far only scratched to surface. For
instance, both the adult uncoordination and the hearing screens
have only covered the second chromosome (10,12). In addition
more sophisticated genetic approaches will undoubtedly be
used in the future, such as using a sensitised system in genetic
modifier screens.
1217
1218
Human Molecular Genetics, 2002, Vol. 11, No. 10
ACKNOWLEDGEMENTS
I thank Daniel Eberl for communicating unpublished results
and Maurice Kernan for providing the beautiful GFP-NompA
fly stock.
REFERENCES
1. McIver, S.B. (1985) Mechanoreception. In Gilbert, L.I. and Kerkut, D.A.
(eds.), Comprehensive Insect Physiology, Biochemistry and Pharmacology.
Pergamon Press, New York/London, Vol. 6, pp. 71–132.
2. Eberl, D.F. (1999) Feeling the vibes: chordotonal mechanisms in insect
hearing. Curr. Opin. Neurobiol., 9, 389–393.
3. Merritt, D.J. (1997) Transformation of external sensilla to chordotonal
sensilla in the cut mutant of Drosophila assessed by single-cell marking in
the embryo and larva. Microsc. Res. Tech., 39, 492–505.
4. Grünert, U. and Gnatzy, W. (1987) Kþ and Caþ þ in the receptor lymph
of arthropod cuticular mechanoreceptors. J. Comp. Physiol., 161,
329–333.
5. Corfas, G. and Dudai, Y. (1990) Adaptation and fatigue of a mechanosensory neuron in wild-type Drosophila and in learning mutants.
J. Neurosci., 10, 491– 499.
6. Walker, R.G., Willingham, A.T. and Zuker, C.S. (2000) A Drosophila
mechanosensory transduction channel. Science, 287, 2229–2234.
7. Hudspeth, A.J. (1997) How hearing happens. Neuron, 19, 947–950.
8. Gillespie, P.G. and Walker, R.G. (2001) Molecular basis of mechanosensory transduction. Nature, 413, 194–202.
9. Hofmann, T., Koch, U.T. and Bässler, U. (1985) Physiology of the femoral
chordotonal organ in the stick insect, Culiculina impigra. J. Exp. Biol., 114,
207–223.
10. Kernan, M., Cowan, D. and Zuker, C. (1994) Genetic dissection of
mechanosensory transduction: mechanoreception-defective mutations of
Drosophila. Neuron, 12, 1195–1206.
11. Eberl, D.F., Hardy, R.W. and Kernan, M.J. (2000) Genetically similar
transduction mechanisms for touch and hearing in Drosophila. J. Neurosci.,
20, 5981–5988.
12. Eberl, D.F., Duyk, G.M. and Perrimon, N. (1997) A genetic screen for
mutations that disrupt an auditory response in Drosophila melanogaster.
Proc. Natl Acad. Sci. USA, 94, 14837–14842.
13. Chung, Y.D., Zhu, J., Han, Y. and Kernan, M.J. (2001) NompA encodes a
PNS-specific, ZP domain protein required to connect mechanosensory
dendrites to sensory structures. Neuron, 29, 415– 428.
14. Moulins, M. (1976) Ultrastructure of chordotonal organs. In Mill, P.J. (ed.),
Structure and Function of Proprioceptors in the Invertebrates. Chapman
and Hall, London, pp. 387– 426.
15. Müller, U. and Littlewood-Evans, A. (2001) Mechanisms that regulate
mechanosensory hair cell differentiation. Trends Cell Biol., 11,
334–342.
16. Adams, C.M., Anderson, M.G., Motto, D.G., Price, M.P., Johnson, W.A.
and Welsh, M.J. (1998) Ripped pocket and Pickpocket, novel Drosophila
DEG/ENaC subunits expressed in early development and in mechanosensory neurons. J. Cell Biol., 140, 143–152.
17. Jarman, A.P. and Jan, Y.N. (1995) Multiple roles for proneural genes in
Drosophila neurogenesis. In Juurlink, B.H.J., Krone, P.H., Kulyk, W.M.,
Verge, V.M.K. and Doucette, J.R. (eds.), Neural Cell Specification:
Molecular Mechanisms and Neurotherapeutic Implications. Plenum Press,
New York, Vol. 3, pp. 97–104.
18. Jarman, A.P. and Ahmed, I. (1998) The specificity of proneural genes in
determining Drosophila sense organ identity. Mechanisms of Development,
76, 117–125.
19. Merritt, D.J. and Whitington, P.M. (1995) Central projections of sensory
neurons in the Drosophila embryo correlate with sensory modality, soma
position, and proneural gene function. J. Neurosci., 15, 1755–1767.
20. Bermingham, N.A., Hassan, B.A., Price, S.D., Vollrath, M.A., Ben-Arie, N.,
Eatock, R.A., Bellen, H.J., Lysakowski, A. and Zoghbi, H.Y. (1999) Math1,
an essential gene for the generation of inner ear hair cells. Science, 284,
1837–1841.
21. Ben-Arie, N., Hassan, B.A., Bermingham, N.A., Malicki, D.M.,
Armstrong, D., Matzuk, M., Bellen, H.J. and Zoghbi, H.Y. (2000)
Functional conservation of atonal and MathI in the CNS and PNS.
Development, 127, 1039–1048.
22. Goulding, S.E., zur Lage, P. and Jarman, A.P. (2000) amos, a proneural
gene for Drosophila olfactory sense organs that is regulated by lozenge.
Neuron, 25, 69–78.
Downloaded from http://hmg.oxfordjournals.org/ at Pennsylvania State University on February 27, 2014
which is the major influence on sense organ structure, but
nothing is known of how it achieves this molecularly (3,19).
Is there an underlying developmental homology between
sense organs (chordotonal organs particularly) and hair cells? A
striking finding suggesting this might be so is that MATH1, one
of atonal’s two closest relatives in mouse, is required for hair
cell determination (20). MATH1 expression can efficiently
rescue the atonal mutation in flies (21), suggesting that the
biochemical characteristics of the Atonal/MATH1 proteins are
conserved. There are also apparent differences between the
phenotypes: atonal is required for precursors of the whole
sense organ whereas MATH1 is not required for support cells or
the sensory neurons, but this might be a rather superficial
distinction. Does this suggest a common ancestor that had a
primordial mechanoreceptor regulated by a proto-atonal? The
answer at present is: primordial sense organ/neuron – possibly;
primordial auditory receptor – probably not. Chordotonal
organs are first and foremost proprioceptors, some of which
have secondarily been adapted (or exapted) to detect sound.
Moreover, the Drosophila proneural gene, amos, which is as
similar to MATH1 as is atonal, is required for olfactory
receptors rather than mechanoreceptors (22). It is human nature
to pick out patterns and similarities among a host of
information. In what way these patterns are meaningful is not
yet clear. To go further, there is a major need to bridge the
upstream developmental aspects and downstream structural/
functional aspects of mechanosensation. Whilst the extent and
level of anatomical and functional homology are debatable, it is
clear that at least some common genetic pathways are involved.
There is no doubt that Drosophila studies will make an impact
on the search for human genes involved in mechanosensation.